Abstract Multidrug-resistant bacteria have evolved into a global crisis on the shortage of available antibiotics. Facing the mounting pressure, it is essential to discover and design next-generation portfolios of novel antimicrobial compositions. Nonspecific interactions are among the most promising approaches for evading antimicrobial resistance. Such interactions include Coulombic attraction between oppositely charged groups and hydrophobic-hydrophobic interactions. It involves a series of coordinated and cascade events for antimicrobial agents to attack bacteria. Because of non-specificity, it would be more challenging for bacteria to develop mechanisms for resistance. On the other hand, strength and selectivity of such interactions are critical to efficacy of antimicrobial killing against bacteria as well as cytocompatibility toward eukaryotic cells. We propose to design local facial amphiphilicity clustered along a macromolecular chain as a new class of antimicrobial compositions that are particularly effective against Gram-negative pathogens. This unique macromolecular composition overcomes many deficiencies of antimicrobial peptides and antimicrobial polymers. First it adopts the facial amphiphilicity from host defense peptides, but not necessarily possessing a helical conformation; second it does not need to overcome a likely impossible global conformational arrangement that antimicrobial polymers need to adapt to make facial amphiphilicity. This new design of macromolecular antimicrobials is demonstrated with novel cationic polymers containing a series of multicyclic natural products including abietic acid, cholic and ursolic acid, which are representatives of tri-, tetra- and penta-cyclic compounds. We define a facial amphiphilic index (FAI) to understand a combination of hydrophobicity and charged groups as well as cross-sectional areas that are needed to penetrate through outer leaflets and further damage cell membranes of bacteria. The most contribution is to correlate facial amphiphilicity with cell compositions for designing selective antimicrobial therapies that could pave a new pathway to fighting vexing bacterial resistance.